Clinical Neuroscience Research 5 (2005) 185199

www.elsevier.com/locate/clires

Cannabis and endocannabinoid modulators:

Therapeutic promises and challenges
Igor Granta,*, B. Rael Cahnb
a
Department of Psychiatry, University of California San Diego, Center for Medicinal Cannabis Research,
9500 Gilman Drive, La Jolla, CA 92093-0680, USA
b
University of California San Diego, Medical Scientist Training Program, University of California San Diego,
Center for Medicinal Cannabis Research, 9500 Gilman Drive, La Jolla, CA 92093-0680, USA

Abstract

The discovery that botanical cannabinoids such as delta-9 tetrahydrocannabinol exert some of their effect through binding specific
cannabinoid receptor sites has led to the discovery of an endocannabinoid signaling system, which in turn has spurred research into the
mechanisms of action and addiction potential of cannabis on the one hand, while opening the possibility of developing novel therapeutic
agents on the other. This paper reviews current understanding of CB1, CB2, and other possible cannabinoid receptors, their arachidonic acid
derived ligands (e.g. anandamide; 2 arachidonoyl glycerol), and their possible physiological roles. CB1 is heavily represented in the central
nervous system, but is found in other tissues as well; CB2 tends to be localized to immune cells. Activation of the endocannabinoid system
can result in enhanced or dampened activity in various neural circuits depending on their own state of activation. This suggests that one
function of the endocannabinoid system may be to maintain steady state. The therapeutic action of botanical cannabis or of synthetic
molecules that are agonists, antagonists, or which may otherwise modify endocannabinoid metabolism and activity indicates they may have
promise as neuroprotectants, and may be of value in the treatment of certain types of pain, epilepsy, spasticity, eating disorders,
inflammation, and possibly blood pressure control.
q 2005 Published by Elsevier B.V. on behalf of Association for Research in Nervous and Mental Disease.

Keywords: Cannabis; Endocannabinoid system; Therapeutics; Dependence

Throughout much of the twentieth century discourse on
marijuana was framed principally in sociopolitical terms
throughout much of the world, and most especially in the
US. The official, governmental point of view in the US,
Canada, and Western Europe was that marijuana was an
addicting drug devoid of therapeutic benefits. Hence, it was
classified as a Schedule 1 agent, i.e. a dangerous drug of no
medical value.
An opposing view, which gradually gained currency
from the 1960 s onward, was that marijuana was a relatively
harmless naturally occurring substance. Most users experi-
enced marijuana as having calming, perhaps soporific
effects, causing transient memory and other cognitive
impairment, and stimulating appetite. While occasional
* Corresponding author. Tel.: C1 858 534 3652; fax: C1 858 534 7723.
E-mail address: igrant@ucsd.edu (I. Grant).
1566-2772/$ - see front matter q 2005 Published by Elsevier B.V. on behalf of Association for Research in Nervous and Mental Disease.
doi:10.1016/j.cnr.2005.08.015
untoward effects were acknowledged (e.g. anxiety
reactions; psychotic phenomena), the general view was
that any alterations in mood and cognition were transient
and that marijuana had little or no addiction potential, at
least as evidenced by apparent lack of physiological
withdrawal symptoms on its discontinuation.
Gaoni and Mechoulams [1] characterization of some of
marijuanas cannabinoid constituents, and in particular, the
identification of delta-9 tetrahydrocannabinol (THC) as the
prime psychoactive drug, stimulated laboratory, animal
model, and human research; however, whereas, some of the
animal studies probed various physiological properties of
the cannabinoids, including some that might have thera-
peutic values, human studies generally concentrated on the
addictive and adverse affects of THC and marijuana. As a
result, by the last decade of the twentieth century it
remained an open question whether the cannabinoids could
have any therapeutic value whatever.
186 I. Grant, B.R. Cahn / Clinical Neuroscience Research 5 (2005) 185199

1. Discovery of the endocannabinoid system

A major paradigmatic shift occurred with the discovery

[2] and cloning [3,4] of delta-9 THC binding sites. The first
discovered cannabinoid receptor was termed CB1. Sub-
sequently, a second receptor, termed CB2 was characterized
[5]. Thereafter, anandamide and 2-arachidonoyl-glycerol
(2-AG), derivatives of arachidonic acid, were identified as
endogenous ligands to CB1 and CB2 [68].
The CB1 receptor is heavily concentrated in the central
nervous system, but is found in other tissues as well,
including liver, gut, uterus, prostate, adrenals, and the
cardiovascular system. CB2 tends to be localized to cells of
immune origin. In the brain the CB1 receptors tend to be
concentrated in sub cortical structures including cerebellum,
basal ganglia, and other limbic lobe circuitries, as well as in
the hippocampus. Though less concentrated, CB1 receptors
are also found in other parts of the cortex. As noted above,
other tissues are also populated by CB1, and in particular,
these include the pituitary, adrenal, GI tract, urinary
bladder, and heart and blood vessels. Of the botanically
derived cannabinoids, delta-9 THC, which is the most
potent psychoactively, binds to both CB1 and CB2
receptors. Delta-8 THC also binds to both, though some-
Fig. 1. Schematic of CB receptor
what less strongly. Cannabidiol binds to none of the
receptors, is devoid of psychoactive effect, yet may have mechanisms to protect the neuron; first, through a
some anti-inflammatory and smooth muscle contraction G-protein coupled mechanism they may reduce NMDA-
inhibitory actions mediated either by a yet uncharacterized
controlled calcium influx; second, since protein kinase A
CB receptor or another mechanism entirely.
(PKA) can stimulate the ryanodine receptor, CB1 agonists,
by reducing PKA may effectively reduce efflux of calcium
from the endoplasmic reticulum (Fig. 2) [9].
2. Structure and function of CB receptors
Cannabinoid CB1 receptors are located at many of the
sites associated with peripheral and central processing of
The CB receptors are part of the super family of
nociceptive messages including medium and large-sized
G-protein coupled receptors. Common features of such
cells of rat dorsal root ganglia (DRG) [10] and spinal
receptors are that they consist of a protein with seven
interneurons [11]. Immunostaining studies report strong
transmembrane regions that can couple to stimulatory or
inhibitory intracellular G-proteins. Such G-proteins can coexpression of CB1 receptors and vanilloid VR1 receptors
then up or down regulate enzymes such as adenyl cyclase in adult rat DRG neurons, which is of particular interest
which can then increase or decrease cyclic AMP (c-AMP) given that anandamide is an agonist both at inhibitory
production. c-AMP in turn can activate protein kinase to cannabinoid receptors and at pronociceptive VR1 receptors
phosphorylate transcription factors such as cyclic AMP [12]. The antinociceptive activity of cannabinoids is
response element binding protein (CREB), which can in mediated through both central and peripheral mechanisms,
turn activate gene expression through production of various as antinociceptive effects of cannabinoids have been widely
messenger RNAs. In the case of activation of the CB1 reported following peripheral, spinal and intracerebroven-
cannabinoid receptor, the typical action is actually tricular administration of different classes of cannabinoid
inhibitory, that is reduction of c-AMP formation (Fig. 1). receptor agonists [13]. While the CB1 receptor has been
Such down regulation of c-AMP is one possible most commonly thought of as the important receptor in
explanation for the putative neuroprotective actions of antinociceptive actions of cannabinoids, recent evidence
CB1 agonists. Neurons can be injured by activation of also suggests the peripheral CB2 receptor agonism can elicit
NMDA receptors that permit entry of calcium, which in turn anti-nociceptive effects [14], and there may be other, as yet
can activate calcium channel receptors (ryanodine unidentified CB receptor or non-receptor based
receptors) intracellularly on the endoplasmic reticulum. mechanisms.
Ryanodine receptors, when activated by calcium can cause The CB1 receptor has also been implicated as essential
further release of calcium into the cytoplasm producing in the development of the feeding response in mice pup
a toxic cascade. CB1 agonists may act through two neonatesin the absence of CB1 receptor signaling,
 I. Grant, B.R. Cahn / Clinical Neuroscience Research 5 (2005) 185199
Fig. 2. Possible mechanism of CB 1 agonist neuroprotection Modified from Zhuang.et.Al.J Neuropharmacology.2005;48:1086-1096
mediated either by CB1 antagonism or genetic CB1
deletion, mice pups do not draw milk from the mother and
die [15,16]. These data suggest that endocannabinoids play
a critical role in survival of the newborn mouse by
controlling milk ingestion. Combined with the finding that
the level of 2-AG in rodent pup brains peaks immediately
after birth [17], it has been suggested that the clinical
application of cannabinoids in treating infant failure to
thrive deserves investigation as well [15].
CB1 receptors are expressed at high levels in brain
regions such as the amygdala, which are implicated in
the control of anxiety and fear [1820]. Pharmacological
[21,22] or genetic [23,24] disruption of CB1 receptor
activity elicits anxiety-like behaviors in rodents, suggestive
of the existence of an intrinsic anxiolytic tone mediated by
endogenous cannabinoids. Further, mice lacking CB1
receptors show strongly impaired extinction but unaffected
acquisition and consolidation of aversive memories. These
effects are associated with elevated levels of endocannabi-
noids in the basolateral amygdala [25], and suggest that
endocannabinoids are crucial for the extinction of aversive
memories.
CB1 receptors have been detected on enteric nerves, and
pharmacological effects of their activation include gastro-
protection, reduction of gastric and intestinal motility and
reduction of intestinal secretion [26]. The digestive
tract also contains endogenous cannabinoids (i.e. the
endocannabinoids anandamide and 2-aracidonylglycerol)
and mechanisms for endocannabinoid inactivation (i.e.
endocannabinoid uptake and enzymatic degradation by
fatty acid amide hydrolaseFAAH).
The CB1 receptor is present in cholinergic nerve
terminals of the myenteric and submucosal plexus of the
stomach, duodenum and colon, and it is probable that
187
cannabinoid-induced inhibition of digestive tract motility is
caused by blockade of acetylcholine release in these areas.
There is also evidence that cannabinoids act on CB1
receptors that are localized in the dorsalvagal complex of
the brainstemthe region of the brain that controls the
vomiting reflex, explaining anti-emetic effects [27]. Endo-
cannabinoids and their inactivating enzymes are present in
the gastrointestinal tract and may also play a physiological
role in the control of emesis, although evidence suggests
that the central effects may be activated at lower doses of
cannabinoids than the peripheral effects [28].
3. Clinical effects of the CB agonists
3.1. Acute effects
Much of our understanding of the acute effects of CB
agonists in humans comes from clinical observations and
anecdotal reports of persons consuming marijuana. The time
course will differ depending on dose and mode of
administration; for example, onset of effects will be more
rapid following smoking than oral ingestion. However, the
qualitative features tend to have similar profiles.
After ingestion by smoking, typical early effects may
include light-headedness, dizziness, euphoria, and some-
times visual-perceptual changes. Tachycardia and hypoten-
sion may be prominent in some individuals. With passage of
time, psychomotor slowing, mild cognitive impairment,
especially in the learning of new information, and change in
sense of time, are frequently reported. Some individuals
experience profound calm and a state of reverie. Others
simply feel somewhat sedated or may experience affective
lability. Uncommon acute effects include anxiety, panic,
188 I. Grant, B.R. Cahn / Clinical Neuroscience Research 5 (2005) 185199
paranoia, and psychotic experiences. Many individuals
report increase in appetite.
Following ingestion through smoking, initial effects may
appear within the first minute, peak at 3060 min, and
gradually dissipate over the next few hours. Oral ingestion
has slower onset (e.g. initial effects in 1530 min, peak
effects in 13 h, and resolution several hours thereafter).
In animal models, the effects of CB agonists such as THC
or synthetic agonists such as WIN-55, 212 and HU 210
produce a characteristic tetrad of neurophysiologic
changes which include (1) reduced ambulation and rearing,
(2) immobility on an elevated ring, (3) hot plate analgesia,
and (4) reduction in core body temperature.
In anesthetized rats and dogs, delta-9-THC produces a
transient pressor response followed by long-lasting hypo-
tension and bradycardia [29]. The hypotensive effect of
delta-9-THC is mimicked by various cannabinoids with a
rank order of potency that correlates well with the affinity of
the same ligands for the CB1 receptor [30]. Administration
of the endocannabinoid anandamide (AEA) to anesthetized
rats also produces a brief pressor response that is followed
by a more prolonged decrease in blood pressure [31]. The
depressor response to AEA is inhibited by coadministration
of the SR141716A CB1 receptor antagonist [31] and is
absent in CB1 receptor null mice [32] reinforcing the notion
that the CB1 receptor is indeed the molecular target
responsible for these observed cardiovascular effects.
3.2. Longer-term clinical effects
If the cannabinoids and their analogs become therapeutic
agents, and particularly, if they are useful for the treatment
of chronic conditions, then the possibility of cumulative
toxicity must be considered. In the instance of drugs with
psychoactive properties, such as the cannabinoids, the
additional issue that their potential for behavioral reinforce-
ment might lead to symptoms of addiction or abstinence
syndrome after drug discontinuation must also be
considered.
The long-term toxicity of cannabinoids in humans
remains largely unknown. The principal reason is that
unlike medically used drugs, for which there is a gradual
accumulation of information based on reasonably accurate
knowledge of cumulative dosage, circumstances of use, and
characteristics of patients, most of our knowledge regarding
the long-term effects of cannabinoids on humans comes
from their uncontrolled recreational use in the form of
marijuana. There are some obvious limitations to infor-
mation gathered in this manner.
3.2.1. Multiple constituents
Human experience with the cannabinoids is based largely
on ingestion of plant material, typically in its smoked form.
Beyond the major active ingredient, THC, this plant
material may consist of as many as 60 other cannabinoids,
whose biological properties are not all fully understood.
Additionally, there may be other biologically active
substances. Thus, even if one were to have accurate
estimates of exposure, whatever, effects were observed
could not necessarily be attributed to THC or some other
molecule. The fact that marijuana is typically smoked also
introduces the possible deleterious effects of various
products of combustion of plant material, toxicities that
may have nothing to do with the cannabinoids per se.
The mix of cannabinoids in plant material poses another
challenge. It is possible that in addition to whatever unique
action each of these molecules has; they may have effects
that interact with each other, either synergistically or
antagonistically. For example, cannabidiol, a common
constituent of marijuana is known to antagonize THCs
depressant effects on smooth muscle contractility [33].
There are also unconfirmed reports that cannabidiol may
antagonize the psychotogenic and anxiogenic effects of
higher doses of THC.
3.2.2. THC concentration is variable in plant material
The concentration of THC varies within and across
plants. THC can be highly concentrated in mature female
unseeded flowers (e.g. 15% of the dry weight of such
flowers can be THC and THC-A [34]) with percentage of
dry weight declining to 0.8% in the leaves, 0.3% in the
stems, and 0% in roots and seeds [34]. The cannabinoid
content also differs according to variety of plant, and such
potency can be increased by crossbreeding. For instance, it
is believed that modern varieties of cannabis grown for
recreational use contain ten times the concentration of THC
of wild varieties. Secular trends have also been evident.
Thus, the typical THC content of a street joint is probably
several times more potent now than it was several decades
ago. These complexities illustrate another level of difficulty
in extrapolating from human, naturalistic exposure to
marijuana to possible adverse effects. Even if the recall of
amount of exposure were accurate, the composition of the
material consumed would be difficult to establish.
3.2.3. Developmental stage
The long-term effects of cannabinoids must also depend
on the developmental stage at which an organism is
exposed. Thus, while there is no solid evidence that adults
who smoke marijuana regularly suffer major long-term
neurological effects [35] it cannot be concluded that
marijuana is safe under all circumstances (see Long-term
effects on development, below).
3.3. Host factors
The exploration of untoward effects of drugs of abuse,
particularly, the neuropsychiatric effects, is complicated by
the fact that those who enter careers of use of illicit
substances are more prone to have psychiatric disorders to
begin with. The comorbidity between heavy substance use
and mood disorders, as well as other psychiatric disorders, is
 I. Grant, B.R. Cahn / Clinical Neuroscience Research 5 (2005) 185199
well documented. In this sense, it may be difficult to
attribute mood disorders to cannabis if the mood disorders
actually contributed to initiation of cannabis use in the first
place. Similarly, individuals with learning disabilities and
attention deficit hyperactivity disorder may experience
scholastic and social frustrations that increase their
likelihood to experiment with drugs such as cannabis.
Again, it is difficult to sort out neurocognitive phenomena
that preceded drug use as opposed to those that may be
consequences of such.
3.3.1. Comorbid drug use
Regular use of cannabis tends to occur in people who
have experience with other legal and illegal recreation
drugs. Heavier cannabis users will more likely be tobacco
smokers, alcohol users, and a subset of heavy cannabis users
will be experienced also with central stimulants, opioids,
central nervous system depressants, hallucinogens, and
inhalants. Sorting out the individual and joint effects of all
these substances is challenging, to say the least.
With these caveats in mind, what is known about the
long-term effects of cannabinoids on the nervous system and
tissues?
3.4. Long-term effects in adults
In terms of neurologic or neurocognitive effects, it has
been difficult to show that there is a consistent, substantial
effect of chronic use on neuropsychological functioning.
While individual studies sometimes have reported deleter-
ious effects on memory in particular, meta-analytic studies
have shown that such effects, if present, are extremely small
[35]. This suggests that if agonist compounds were to
become medicines, we would expect them to have a good
margin of safety even under conditions of longer-term
prescription use. Of course, it may be the case that more
potent synthetic CB agonists could have deleterious effects
that have not been possible to demonstrate with THC and
marijuana, either because THC is not as potent a CB binder,
or because of some other unique pharmacokinetic and
pharmacodynamic properties.
Cannabinoids can increase susceptibility to viral and
protozoal infection in animal models, presumably through
their immunosuppressive effects on macrophages, T-lym-
phocytes, and natural killer cells [36]. Interestingly, even in
some animal models the effects on viral infection can differ,
depending on the model. For example, Peterson et al. [37]
noted that the synthetic cannabinoid agonist WIN 55,212-2
inhibited HIV-1 expression in CD4 and lymphocyte and
microglial cell cultures. Nonetheless, the safety of admin-
istration of these agents to AIDS and cancer patients might
be questioned. Encouragingly, long-term surveys of HIV-
positive patients have shown no link between dronabinol
(synthetic THC) use or cannabis smoking and average
T-cell counts or progression to AIDS [38,39]; and a clinical
study in which marijuana was administered under controlled
189
conditions to HIV positive patients also showed no adverse
effects on immune functioning [40].
3.5. Long-term effects on development
While observations of adult humans who are regular
users of marijuana have failed to demonstrate unequivocal
long-term toxicity, it is evident that the cannabinoids, or any
other psychoactive drug for that matter, might not be so
benign in developing organisms. The few sets of human
observations will be reviewed below; however, because of
the obvious difficulties in controlling all of the important
sources of variation in human studies, animal models might
be particularly informative in this instance.
A series of rodent studies have been conducted, generally
exposing rats to varying concentrations of THC for differing
periods of time during their pre-pubertal stage. Although
some studies have failed to detect longer-term impacts on
adult behavior, the majority tend to show that chronic high
dose exposure of developing rats to THC can produce
learning and performance deficits of a type that is similar to
that found in animals with certain types of hippocampal
lesions [41]. Further, morphometric and neurochemical
studies of animals sacrificed after such exposure indicate
there may be neuronal injury in the hippocampus as
evidenced by breakage of axonodendritic contact regions,
with increases in extracellular space, and reduction in
synaptic density in the hippocampal CA3 region [41].
Neuronal culture models suggest that THC may produce
DNA fragmentation and nuclear shrinkage suggestive of
apoptosis [42,43].
The translation of these rodent and in vitro experiments to
our understanding of the effects of cannabis, as it is used by
people, on child and adolescent development is not
straightforward. First, it is evident that even in rodents the
demonstration of some of these effects requires prolonged
high dosage exposure to THC or its analogs during the
maturational period. In terms of dose, typical daily
administration ranges from 1060 mg per kilogram per day
of THC. For a 70 kg human, this would mean administering
up to 4.2 kg of THC daily (or smoking 420 high quality joints
containing 10% THC and delivering 100% bioavailability).
While it is recognized that such simple linear transformations
are not appropriate given our understanding of higher
metabolic rates and generally different kinetics and dynamics
in smaller animals, nevertheless, even after such caveats are
taken into account, the daily dosages required to produce
these effects must be considered impressive.
The proportion of the developing animals time exposed
to such large amounts of THC must also be noted when
considering relevance to the human situation. Rodents must
typically be dosed for 36 months, i.e. up to 20% of their
lifespan. In human terms, considering a life expectancy of
70 years, this would translate into a child or adolescent
being exposed daily at high doses for 714 years of their
developing life, a highly unlikely scenario.
190 I. Grant, B.R. Cahn / Clinical Neuroscience Research 5 (2005) 185199
Species differences must also be considered. For
example, similar behavioral and neuroanatomic changes
have been difficult to demonstrate consistently in primate
models of chronic cannabis exposure. Furthermore, rodents
may respond more than some other species with significant
release of corticosterone to THC administration. Corticos-
terone itself can produce injury to the hippocampus, which
may be difficult to sort out from the direct effects of the
cannabinoids.
Given difficulties in extrapolating from animal models,
what can be gleaned from the few studies that have been
conducted with human development? The Ottawa Prenatal
Prospective Study (OPPS) has produced several reports that
have examined the link between prenatal exposure to
cannabis and subsequent child development. Neither in a
56-year-old follow-up [44] nor in the 912-year-old
follow-up [45] did the authors note any relationship between
prenatal marijuana exposure and various school achieve-
ment measures. Data from the Maternal Health Practices
and Child Development study (MHPCD) in Pittsburgh
reported possible weak effects for impairment in some
measures of academic achievement related to mothers use
of marijuana in the first and second trimester [46]. However,
in that study the authors believed that the childs anxiety and
depression mediated some of this underachievement, and it
was not clear what role prenatal marijuana exposure played
in such mood changes in the child. Furthermore, though
mothers education was included in a multivariate model, it
was not clear from the report whether parental IQ, which
may have an independent effect on child intellectual
performance, as well the mothers decision to use marijuana
while pregnant was considered. The complex bidirection-
alities of cannabis and neurodevelopmental trajectory were
illustrated in a report by Pedersen et al. [47], which was
based on a prospective longitudinal study of a national
sample of 2436 adolescents in Norway. The authors found
that early conduct problems in children were significant
predictors of later initiation of cannabis use. While
neurocognitive measures were not reported, based on
other research it might be expected that children with
early conduct problems may score worse on scholastic and
neuropsychological tests. As these would also be the
children more likely to initiate cannabis use, a difficulty
arises in subsequently sorting out the effects of dispositional
factors and drug on adolescent intellectual development.
In summary, rodent models suggest that heavy prolonged
exposure of developing animals to THC can produce
neurobehavioral deficits and neuroanatomic changes, par-
ticularly in the hippocampus. There are insufficient data
from primate models to reach conclusions on THCs effect
on primate development. The translation from animal
models to typical human experience, given species-specific
differences, large dosages and chronicity of use required, is
questionable. Current human observations on the effects of
marijuana on development are sparse and contradictory.
4. Addiction potential of cannabinoids
It is a common observation that humans find their
experience with the cannabinoids in the form of marijuana
to be sufficiently rewarding that some of them choose to
revisit the experience at least on an occasional basis, with a
smaller proportion becoming regular users. Increasingly,
animal models have begun to delineate the molecular and
physiological bases for this reinforcement; however,
translation from such models to the human experience has
proved difficult. Initially, animal models based on admin-
istration of THC provided inconclusive results, depending
on species and exact conditions of administration. The
discovery of CB receptor antagonists provided the first
clear-cut demonstrations that animals chronically exposed
to THC or synthetic agonists could be precipitated into a
withdrawal state by such antagonists.
The lines of evidence from animal models indicating that
THC and the CB1 agonists share some of the motivational
and reinforcing properties of other drugs of abuse have been
summarized by Maldonado and Rodrguez de Fonseca [48].
Thus, THC can be demonstrated to provide selective
discriminative stimulus effects, which can be prevented by
the CB1 antagonist SR141716A. Under suitable conditions,
animals will demonstrate preference for THC, which can
also be suppressed by CB1 blockade. Interestingly,
conditioned place preference is suppressed in m-opioid
receptor knockout mice, indicating interplay between the
opioid and the cannabinoid systems. It should be noted that
preference is dose dependent (animals find higher doses of
THC to be aversive) and also dependent on pre-exposure
(nave animals tend to find THC aversive).
To a variable degree THC can be shown to enhance
intracranial self-stimulation (ICSS), the magnitude of the
effect differing across species. Once again, CB1 blockade
reduces THC induced ICSS and naloxone can block THC
enhancement of ICSS. While intravenous self-adminis-
tration (IVSA) paradigms involving THC itself have proved
to be unreliable, experiments with synthetic CB1 agonists
such as WIN 55 212-2 can produce IVSA, which is
prevented by CB1 antagonists, and, in some species by
opioid antagonists, as well.
Animal models also indicate that tolerance develops to
the chronic administration of CB1 agonists. This tolerance
extends to their hypothermic, analgesic, anticonvulsant,
cataleptic, and cardiovascular effects. Chronic adminis-
tration of CB1 agonists results in reduced density and
sensitivity of CB1 receptors.
In terms of withdrawal phenomena, animal experiments
with chronic THC administration were not able reliably
to produce an abstinence syndrome. However, sudden
discontinuation of the synthetic agonists can produce such
a syndrome, which is best elicited through administration of
CB1 antagonists. In rodents, various locomotor signs of
withdrawal have been observed including wet dog shakes,
 I. Grant, B.R. Cahn / Clinical Neuroscience Research 5 (2005) 185199
hyperlocomotion, ataxia, front paw rubbing, licking, biting,
and scratching.
There are fewer data in regard to tolerance and
withdrawal symptoms in humans. Evidence from a handful
of interview and clinical laboratory studies indicate that
sudden discontinuation of regular use of marijuana can
result in irritability, nervousness, tension, restlessness,
reduced appetite, sleep difficulties, dysphoria, and possibly
craving [49,50]. These data are reviewed in detail by
Budney et al. [51].
These symptoms have some characteristics in common
with, albeit are much less severe than those experienced in
opioid withdrawal. A notable difference between cannabi-
noid abstinence and opioid abstinence is the presence of
severe physiological manifestations in the latter, not found
in the former. These include opioid withdrawal related
symptoms such as achiness, piloerection, diarrhea, sweat-
ing, stuffy nose, muscle spasms, etc.
In summary, tolerance, dependence, and withdrawal
effects can be demonstrated in certain animal models, and
have also been reported in humans. The pharmacokinetics,
and perhaps the pharmacodynamics of THC (e.g. slow
elimination of THC and its byproducts) may attenuate
withdrawal to a subclinical level among humans, thus the
effect not being notable in any except very heavy users who
suddenly discontinue. As cannabinoids advance into
medical practice, the synthetic CB agonists, having different
kinetics and dynamics, may produce more (or perhaps less)
signs of tolerance, dependence, and withdrawal. As such
agents are developed and evaluated, the complex inter-
actions between the cannabinoid and opioid systems will
require continued study.
5. Marijuana and cannabinoids as medicine
Although references to potential medicinal properties of
cannabis date to ancient times, and despite cannabis being
included as a medication in Western pharmacopeias from
the nineteenth through the early twentieth centuries, there is
still no body of reliable information on possible indications
or efficacy. In part, slow progress can be attributed to
difficulties in identifying the active ingredients in cannabis;
THC was not actually characterized and identified as the
main psychoactive substance until 1965. The chemical
properties of the cannabinoids, for example their virtual
insolubility in water, and the fact that they consist of oily
liquids at room temperature has posed further challenges in
formulation and administration. Increased governmental
concerns about the abuse potential of marijuana and hashish
also created a regulatory climate in many Western countries
that emphasized the negative properties of these substances
and absence of any documented medicinal properties, thus
discouraging research into therapeutics.
Cultural and attitude changes in the latter half of the
twentieth century in many Western countries resulted in
191
large groups of mainstream adults and adolescents
experimenting with marijuana. The scarcity of obvious
acute serious toxic effects, and lack of consistent infor-
mation on longer-term adverse effects has lead to more
recent attitudinal changes in many Western societies that
have re-opened the possibility of use of cannabis as a
medication.
For example, the ninth report for the House of Lords
Select Committee on Science and Technology of the British
Parliament in 1998 concluded that cannabis most probably
did have genuine medical applications that clinical trials of
cannabis for the treatment of multiple sclerosis and chronic
pain should be mounted as a matter of urgency, that
cannabis should be reclassified to a less restrictive schedule,
and that research should be promoted into alternative modes
of administration [52]. Similarly, the report of the Senate
Special Committee on Illegal Drugs of the Parliament of
Canada recommended that Health Canada amend the
Marijuana Medical Access Regulations to allow compas-
sionate access to cannabis and its derivatives. More
specifically, the Committee called for new rules regarding
eligibility, production, and distribution with respect to
cannabis for therapeutic purposes, and stated that research
on cannabis for therapeutic purposes was essential[53].
More recently still, the Netherlands in March 2003 changed
its opium law to allow doctors to prescribe cannabis through
pharmacies. In the USA, an increasing number of states,
mostly in the West passed laws or initiatives permitting
patients to have access to marijuana for medicinal purposes
with physician prescription. The status of these state laws
remains in doubt as contradictory court decisions continue
to try to resolve whether state or federal statutes are pre-
eminent. In California, one spin-off of the voter passed
Compassionate Use Act(Proposition 215), which envi-
sions access to marijuana for patients under medical
supervision, was the establishment in 1999 by the
legislature of the State of California of the Center for
Medicinal Cannabis Research (CMCR) at the University of
California. The CMCR represents the first comprehensive
program in clinical research on marijuana ever to be
conducted in the United States and is currently supporting
approximately 12 clinical studies with patients with various
disorders including severe AIDS (and other) related
peripheral neuropathy, spasticity in multiple sclerosis, and
delayed nausea and vomiting in cancer. Similarly, as a
follow-on to Canadas Senate Report, the Canadian
Institutes of Health Research is considering applications
for the first modern era clinical trials of cannabis in that
country.
5.1. Results of earlier research with cannabis, THC,
and its synthetic analogs (1970searly 1990 s)
The results of earlier clinical studies have been reviewed
thoroughly in several reports, and will not be presented in
detail here [5255]. In brief, there were contradictory
192 I. Grant, B.R. Cahn / Clinical Neuroscience Research 5 (2005) 185199
findings in human studies on pain, with some research
suggesting that THC relieved cancer pain about as well as
60 mg of codeine [56,57] and that levonantrodol, a synthetic
THC-like cannabinoid was effective in post-operative and
trauma pain [58]. On the other hand, Raft et al. [59] found
no effect of THC on the pain of tooth extraction, and Clark
et al. [60] found some suggestion that moderate to high
doses of THC actually produced hyperalgesia.
A number of the earlier studies examined the effects of
THC and its analogs on chemotherapy induced nausea and
vomiting. Generally speaking, THC and its analogs were
found to be somewhat effective [61,62]. The efficacy of
THC, nabilone, and levonantrodol (synthetic analogs of
THC) was comparable to that of prochlorperazine [6366],
but not as good as that of metoclopramide [67]. The results
were sufficiently favorable that in 1985 the US FDA
approved dronabinol (synthetic THC) for use in nausea and
vomiting.
In the 1990 s, clinical trials indicated that dronabinol
could improve appetite and increase weight in cancer
cachexia [68] and was useful in improving the nutritional
status and appetite in persons with advanced HIV disease
and AIDS wasting [6971]. The FDA approved dronabinol
as an appetite stimulant for AIDS related weight loss in
1992.
Considerable anecdotal evidence and some animal
studies have suggested that the cannabinoids might be
useful in treatment of spasticity, movement disorders, or
dystonias. Until recently, there have been very few properly
designed studies, and their results have been contradictory
[54]. Anecdotal reports of possible marijuana benefits have
been particularly numerous in regard to spasticity and
tremor of multiple sclerosis. However, prior to the early
1990 s only one placebo controlled trial was completed with
patients with multiple sclerosis [72]. This study involved
13 patients with MS and spasticity. The authors concluded
that doses of THC at 7.5 mg daily or above produced
significant improvement in spasticity, compared to placebo.
5.2. Recent and on-going studies with cannabis, THC,
and their synthetic analogs
Stimulated by the increased pace of discoveries related to
the endocannabinoid system, and supported by changes in
social acceptance of the possibility of the cannabinoids as
medicines in many industrialized countries, there has been a
renewal of interest and activity in clinical research on
cannabis and related substances. The results of an entire
program of research from the Center for Medicinal
Cannabis Research at the University of California should
be forthcoming in the next several years. These studies
involve primarily smoked marijuana. In the United King-
dom and Europe several trials have been conducted with
novel oral-mucosally administered extracts of cannabis,
involving approximately equal amounts of THC and
cannabidiol (approximately 2.5 mg of each) delivered
through a metered dose device (Sativex-GW Pharmaceu-
ticals). The initial results of experience with Sativex are
beginning to be reported.
In a study of 160 outpatients with multiple sclerosis,
there was no significant benefit for Sativex versus placebo
on the primary outcome measure, a visual analog scale score
for the patients most troublesome symptom. However, the
authors do report significant reduction in self-reported
spasticity. A second group of patients with MS were
evaluated for changes in symptoms of bladder dysfunction
during an open label study [73]. Improvement was noted in
number of incontinence episodes, urinary frequency, and
nocturia.
Three other studies with cannabinoids and multiple
sclerosis have recently been reported. The results have been
marginal or ineffective. A study of 16 patients found no
treatment benefit for spasticity and worsened patient global
impression score [74.] A study of 57 patients by Vaney et al.
[75] found no statistically significant difference to placebo
in the intention to treat analysis, although sub-analyses
suggested some benefit for spasticity ratings. Similarly, a
large multi-site study of 630 patients randomly assigned to
receive THC, cannabis extract, or placebo failed to
demonstrate improvement in spasticity on objective rating.
However, self-report ratings did suggest some benefit, and
there was a suggestion that the THC group had improve-
ment in walking [76]. In summary, newer studies on
multiple sclerosis spasticity continued to show inconsistent,
and, at best, modest results. Two CMCR studies are still on-
going and these may help determine whether it might be
useful to pursue molecules based on the cannabinoids in
future MS studies.
In regard to newer studies on pain, Berman et al. [77]
reported on the results of two GW produced mucosal sprays,
Sativex (about equal composition THC and cannabidiol)
and GW2000-02 (primarily THC) in 48 patients with
neuropathic pain from brachial plexus avulsion. Based on
the primary outcome measure, which was a fall of at least 2
points in a mean pain severity score, both active treatments
were not effective. There were, however, were some
improvements both in pain and sleep measures. Again,
these data suggest at best modest therapeutic efficacy of
these cannabinoid preparations.
In regard to movement disorders, historic data have not
been promising. A recent study of cannabis extract failed to
show improvement in Parkinsonian dyskinesia [78].
5.3. Potential therapeutic opportunities with novel agonists,
antagonists and modifiers of endocannabinoid transport
and metabolism
Following the discovery of the cannabinoids and some of
their molecular targets, it is now clear that in theory, at least,
the diseases and illnesses that may be susceptible to
treatment via modulation of cannabinoid system are many.
This is evidenced by the recent proliferation of lengthy
 I. Grant, B.R. Cahn / Clinical Neuroscience Research 5 (2005) 185199
reviews on the clinical implications for cannabinoid
therapeutics [38,7986]. The list of conditions includes
gastrointestinal disorders (including inflammatory bowel
disease), obesity, asthma, glaucoma, cancer, Parkinsons
disease, multiple sclerosis and other diseases of defective
immunomodulation, cardiovascular disease, hypertension,
cystic fibrosis, stress-related disorders, nausea, vomiting,
drug addiction, and pain. A brief review of the main
possibilities and their possible molecular mechanisms
follow below.
5.4. Appetite
Anandamide is capable of increasing food intake in rats
[87], while the antagonist SR-141716A inhibits the intake of
food [8890] and is currently being evaluated as an anti-
obesity treatment with good results (see below). The
underlying circuitry responsible for the therapeutic efficacy
of cannabinoids in stimulating appetite is not yet known,
although it is probably related to the fact that the CB1
receptor, anandamide, and 2-AG are present in the
hypothalamus, which is known to be associated with
feeding [91]. It is of note that evidence for a function of
the endogenous cannabinoid system in feeding has been
obtained for the primitive invertebrate Hydra vulgaris [92],
pointing to a very ancient history of the endocannabinoid
system in the regulation of feeding, greatly preceding the
evolution of the hypothalamic control of appetite seen in
vertebrates.
One of the currently accepted uses of cannabinoid
therapy in the US and many European countries is a
synthetic delta-9-THC preparation (dronabinol, Marinol)
and its synthetic analogue LY109514 (nabilone, Cesamet),
both of which are approved in several counties primarily for
nausea and emesis associated with cancer chemotherapy but
also used for the stimulation of appetite in cancer and HIV
infection. Studies have found dronabinol to be effective in
stimulating appetite in both cancer patients [93] and HIV
infected patients [94]. Interestingly, endocannabinoids are
present in breast milk, 2-AG levels being much higher than
those of anandamide [95].
Regarding possible treatment for obesity mediated
through the cannabinoid system, the Sanofi-Synthelabo
Research group recently presented the results of a phase III
clinical trial on the effects of the selective CB1 antagonist
SR141716A (Rimonabant) in obese patients with hyperli-
pidemia [96]. While Rimonabant had no effect on taste, it
induced a significant decrease of hunger, caloric intake, and
body weight in obese patients in comparison with placebo
72% of the patients showed at least a 5% reduction in weight
and 44% of patients at least a 10% reduction. Impressively
there was also an increase in HDL cholesterol, a decrease in
triglyceride values and reductions in both glucose and
insulin values after an oral glucose tolerance test. These
results indicate that Rimonabant may become a therapeutic
drug in obesity in the near term.
193
5.5. Gastrointestinal
Historically, marijuana was prescribed for the treat-
ment of diarrhea as well as inflammatory diseases of the
bowel [97]. It now appears that the range of
gastrointestinal disorders that may be amenable to
treatment with cannabinoid therapeutics is quite broad,
including nausea and vomiting, gastric ulcers, irritable
bowel syndrome, ulcerative colitis, Crohns disease,
secretory diarrhea, paralytic ileus and gastroesophageal
reflux disease [26,98].
The therapeutic possibilities of cannabinoids have been
demonstrated in a number of these diseases in both
animal models and clinical trials. For example, a recent
report showed that experimental colitis is more severe in
CB1-deficient mice than in wild-type littermates, and
furthermore, that pre-treatment with a CB1 antagonist in
wild-type mice elicits a similar potentiated susceptibility
to this experimental colitis model [97]. Further recent
evidence suggests the possibility that CB2 receptors in
the rat intestine can help reduce the increase of intestinal
motility induced by endotoxic inflammation [99]. By
minimizing the adverse psychotropic effects associated
with brain cannabinoid receptors, the CB2 receptor
represents a promising molecular target for the treatment
of motility disorders from the perspective of reduced side
effects.
5.6. Cardiovascular
It has been long recognized that the cannabinoids
produce cardiovascular effects in vivo. In humans, the
most consistent cardiovascular effects of both marijuana
smoking and i.v. administration of delta-9-THC are
peripheral vasodilation and tachycardia [29]. These effects
manifest themselves as an increase in cardiac output,
increased peripheral blood flow, and variable changes in
blood pressure (usually reduced).
What is less well recognized, but of potential clinical
importance, is that a variety of observations suggest that
endocannabinoids have protective effects on the cardiovas-
cular system particularly in shock and myocardial ischaemia
[100]. For example, CB1 antagonism increases blood
pressure and decreases survival time in rats, which are in
hemorrhagic shock as a result of the removal of 50% of
blood volume whereas cannabinoid agonists increase
survival [101]. Recent evidence suggests that cannabinoids
reduce infarct size associated with ischaemia/reperfusion in
rat-isolated hearts and the effect is blocked by CB
antagonists SR141716A or SR144528 [100]. In the next
few years, there is likely to be a concerted effort to uncover
the molecular determinants of this cardioprotective effect,
opening up the doorway to the application of cannabinoi-
dergic modulators in the treatment of cardiovascular
disease.
194 I. Grant, B.R. Cahn / Clinical Neuroscience Research 5 (2005) 185199
5.7. Cancer
The antiproliferative properties of cannabis compounds
were first reported almost 30 years ago by Munson et al.
[102], who showed that THC inhibits lungadenocarcinoma
cell growth in vitro and after oral administration in mice.
Further studies in this area were not carried out until the late
1990 s. Several plant-derived (for example, THC and
cannabidiol), synthetic (for example, WIN-55, 212-2 and
HU-210) and endogenous cannabinoids (for example,
anandamide and 2-arachidonoylglycerol) are now known
to exert antiproliferative actions on a wide spectrum of
tumour cells in culture [103,104]. More importantly,
cannabinoid administration slows the growth of various
tumour xenografts, including lung carcinomas, gliomas,
thyroid epitheliomas, skin carcinomas and lymphomas. The
molecular determinants for these processes is not yet known
and quite complicated, varying depending on the cancer cell
type or process studied. One process that has been observed
in both in vivo and in vitro studies of glioma is that
cannabinoid agonists were shown to activate apoptosis in
transformed cells through ERK signaling and AKT path-
ways, resulting the production of ceramide and subsequent
apoptotic cell death [105,106]. Other observed processes in
conjunction with reduced cancerous growth include
sustained adenylyl cyclase inactivation and ERK activation
with decreased growth-factor receptor signaling and
decreased angiogenesis and metalloproteinase expression
[103]. As these processes are delineated, the possible role of
phyto and synthetic cannabinoids and other CB1 agonists as
antineoplastics will need to be explored.
5.8. Neuroprotection
There is evidence supporting a neuroprotective role for
cannabinoids, and some of this is presented in the subsequent
section on Multiple Sclerosis. It seems that the endocanna-
binoid system facilitates neuroprotective activity at baseline
and can be upregulated when injury occurs [107109]. In
support of the general finding that cannabinoids act in a
neuroprotective manner, glutamate toxicity has been shown to
be reduced in mice pretreated with either THC or cannabidiol
[110,111]. In support of the role of the endocannabinoid
system in providing neuroprotective relief from brain injury, it
has been reported that rat neonatal brain produces signifi-
cantly more anandamide and its phospholipid precursor after
injury than controls [112] whereas, experimental stroke has
been found to cause the induction of CB1 receptor expression
[113]. After a relatively mild head trauma, anandamide, but
not 2-AG, levels in young rat brains were found to be
significantly elevated [114]. In addition, others have found
that closed head injury (CHI) in mice causes strong
enhancement of 2-AG production and that exogenous 2-AG
administration after CHI in mice leads to significant reduction
of brain edema, better clinical recovery, reduced infarct
volume and reduced hippocampal cell death compared with
controls [115]. In farct volumes of spontaneously hyperten-
sive rats subjected to permanent middle cerebral artery
occlusion were smaller in animals treated with dexanabinol
[116]. In sum, it appears that the cannabinoid system is
upregulated in response to various brain insults, perhaps
representing an attempt to provide endogenous neuroprotec-
tive actions, and it is likely that therapeutic strategies based on
modifying endocannabinoid activity will prove useful.
5.9. Multiple sclerosis
The studies on neuroinflammation in animal models of
multiple sclerosis have been encouraging. Data from
experiments with rats and guinea-pigs [117,118] have
indicated that cannabinoid agonists decrease signs of
experimental autoimmune encephalomyelitis (EAE), a
mouse model of MS. Mouse studies of EAE have shown
decreased neurodegeneration from the administration of
cannabinoid agonists and greatly increased susceptibility to
the disease in CB1-Knock out mice, and the important
neuroprotective role of CB1 (as evidenced by greatly
increased neurodegeneration in CB1-KO mice) has been a
focus in such studies [119]. A variant of EAE and second
model of MS, chronic relapsing experimental allergic
encephalomyelitis (CREAE), has shown very robust
sensitivity to cannabinoid agents as well. For example,
Baker et al. [120] have investigated the role of CB1 vs. CB2
cannabinoid receptors in cannabinoid-induced suppression
of the spasticity and tremor of mice with CREAE, reporting
that both CB1 and CB2 receptors may play a roleCB2
possibly through their presence on immune cells in the CNS
which may be signaled to down-regulate their reactivity
through cannabinoid agonism [120,121].
Clinical studies on marijuana and cannabinoids in the
treatment of multiple sclerosis (MS) have focused on
the reduction of muscle spasticity and pain. Unlike the
preclinical data, human studies have shown mixed results,
as noted above. It remains to be seen whether novel
molecules, optimized for modifying neural excitability,
inflammation, or both may be useful in MS treatment.
Future trials may need to differentiate patients who have
more signs of inflammation (e.g. relapsing-remitting cases)
versus neuronal injury (e.g. progressive cases). For
example, is it possible that upregulation of microglial CB2
receptors early in the course of disease might reduce
inflammatory injury in the CNS? [122].
5.10. Pain
The cannabinoid signaling system functions as a parallel
but distinct mechanism from the opioids in modulating pain
responses. Once again, the preclinical research which
indicates strong anti-nociceptive effects in a number of
animal models is much more convincing than the clinical
trials to date. For example, in the animal models the
antinociceptive potency of delta-9-THC is no less than that
 I. Grant, B.R. Cahn / Clinical Neuroscience Research 5 (2005) 185199
of morphine, an agent known to induce receptor-mediated
analgesia, and a number of cannabinoids show even greater
potency than delta-9-THC in specific pain tests [123].
Human pain studies with marijuana and THC analogues
have produced results that are weaker than animal data
would predict. Evident sources of variation that need to be
addressed are nature of pain (e.g. surgical, inflammatory,
neuropathic) and the possibility that there is an inverted U
shaped effect (e.g. medium dose is antinociceptive, high
dose is hyperalgesic), and the possibility that for some types
of pain the cannabinoid agonists exert their effects through
non-CB receptor mechanisms. In this regard, Salim et al.
[124] have shown that a synthetically modified compound
derived from the THC metabolite THC-11-oic acid, termed
ajulemic acid, may have analgesic and anti-allodynic
effects. Ajulemic acid does not bind strongly to CB
receptors and does not have psychotropic effects. Salim
et al. [124] suggest that its antinociceptive action might
involve inhibition of cyclooxygenase-2. Similarly, the
endogenous anandamide analogue N-palmatoylethanola-
mine (PEA) appears to exhibit anti-inflammatory and
analgesic effects in experimental models of neuropathic,
inflammatory and visceral pain through non-CB1 or CB2
receptor mechanisms [28].
5.11. Stress and anxiety
Several converging lines of evidence suggest cannabi-
noid therapeutic possibilities in the treatment of stress-
related disorders. One study of animal models using a fatty
acid amide hydrolase (FAAH) inhibitor to potentiate
endogenous levels of cannabinoid signaling has substan-
tiated this. FAAH inhibitors interfere with hydrolysis of
anandamide, increasing its availability. The FAAH Inhibitor
URB597 does not display a typical cannabinoid profile in
live animals but does exert several pharmacological effects
that might be therapeutically relevant. One such effect, the
ability to reduce anxiety-like behaviors in rats, was
demonstrated in the elevated zero maze test, and the
isolation-induced ultrasonic emission test [125]. The zero
maze is based on the conflict between an animals instinct
to explore its environment and its fear of open spaces where
it may be attacked by predators. Benzodiazepines and other
clinically used anxiolytic drugs increase the proportion of
time spent in, and the number of entries made into, the open
compartments and in a similar fashion, URB597 elicits
anxiolytic-like responses at a dose (0.1 mg/kg, intraper-
itoneal) that corresponds to that required to inhibit brain
FAAH activity. These effects are prevented by the CB1-
selective antagonist SR141761A. Similar results were
obtained in the ultrasonic vocalization emission test,
which measures the number of stress-induced vocalizations
emitted by rat pups removed from their nest. These results
suggest that inhibition of intracellular FAAH activity may
offer an innovative target for the treatment of anxiety [126],
which is also a feature of marijuana withdrawal [50,51,127].
195
Forebrain sites that might be implicated in such actions
include the basolateral amygdala, the anterior cingulate
cortex and the prefrontal cortex, all key elements of an
emotion circuit that contains high densities of CB1
receptors [18,19].
5.12. Drug addiction
While the development of a rodent model of delta-9-
THC self-administration has so far been unsuccessful [128],
it is clear that the endocannabinoid system, acting through
CB1, is actively involved in the dopaminergic mesolimbic
brain reward circuit [128,129]. Cannabinoids enhance the
release of dopamine in the nucleus accumbens, an effect due
to an enhanced firing of mesolimbic dopaminergic neurons
[130]. Within the central nervous system, the D2 and CB1
receptors are densely expressed in the basal ganglia [131]
and recent results indicate that the acute drug-induced
dopamine release in the nucleus accumbens (NAc) is in fact
mediated by CB1 receptors for a wide class of abused drugs
[128,132]. For example, alcohol-induced increase in
dopamine in nucleus accumbens dialysates in C57BL/6
mice was completely inhibited by pre-treatment with the
SR141716A or deletion of CB1 receptors in mice (CB1
receptor knockout), suggesting an interaction between the
cannabinoidergic and dopaminergic systems in the reinfor-
cing properties of alcohol addiction [132,133].
Findings from preclinical studies suggest that ligands
blocking CB1 receptors (e.g. SR 14176A/Rimonabant)
might offer a novel and possibly efficacious approach for
patients suffering from drug dependence that may be
efficacious across different classes of abused drugs.
5.13. Glaucoma
Cannabinoids have the potential of becoming a useful
treatment for glaucoma, as they seem to have neuroprotec-
tive properties and effectively reduce intraocular pressure.
The converging evidence supporting their use for not only
intraocular pressure but also for their neuroprotective effects
has prompted a number recent reviews highlighting their
promise for this eye disorder [134136]. Pharmacological
and histological studies support the direct role of ocular
CB1 receptors in the intra-ocular pressure (IOP) reduction
induced by cannabinoids. The anatomical distribution of
cannabinoid receptors suggests a possible influence of
endogenous cannabinoids on aqueous humour outflow and
on aqueous humour production. Despite the earlier belief in
a central mediation of the effects of cannabinoids on IOP,
recent work has now shown that it the effects are local in
naturefor example, two groups have shown that the IOP-
lowering effect of topically-applied synthetic CB1 agonists
can be antagonized by topically pretreating the animals with
the CB1 antagonist SR [137,138].
196 I. Grant, B.R. Cahn / Clinical Neuroscience Research 5 (2005) 185199
5.14. Summary
The discovery of an endocannabinoid signaling system
has opened new possibilities for research into understanding
the mechanisms of marijuana actions, the role of the
endocannabinoid system in homeostasis, and the develop-
ment of treatment approaches based either on the
phytocannabinoids or novel molecules. CB1 agonists may
have roles in the treatment of neuropathic pain, spasticity,
nausea and emesis, cachexia, and potentially neuroprotec-
tion after stroke or head injury. Agonists and antagonists of
peripheral CB receptors may be useful in the treatment of
inflammatory and autoimmune disorders, as well as
hypertension and other cardiovascular diseases. CB1
antagonists may find utility in management of obesity and
drug craving. Other novel agents that may not be active at
CB receptor sites, but might otherwise modify cannabinoid
transport or metabolism, may also have a role in therapeutic
modification of the endocannabinoid system. While the
short and long term toxicities of the newer compounds are
not known, one must expect that at least some of the acute
effects (psychotropic effects; hypotension) may be shared
by CB agonists. While there are few, long-term serious
toxicities attributable to marijuana, extrapolation to newer
and more potent agonists, antagonists, and cannabinoid
system modulators cannot be assumed. CB1 agonists have
the potential in animal models to produce drug preference
and drug seeking behaviors as well as tolerance and
abstinence phenomena similar to, though not generally as
severe as those of other drugs of addiction. There is
increasing evidence from human observations that with-
drawal from the phytocannabinoids can produce an
abstinence syndrome characterized primarily by irritability,
sleep disturbance, mood disturbance, and appetite disturb-
ance in chronic heavy users, therefore, such possible effects
will need to be considered in the evaluation of newer shorter
acting and more potent agonists.
Acknowledgements
Supported by the University of California Center for
Medicinal Cannabis Research and in part by the NIGMS
Medical Scientist Training Grant #T32 GM07198.
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